Prognostic value of the fibrinogen albumin ratio index (FARI) in nasopharyngeal carcinoma patients undergoing radiotherapy

There is mounting evidence that malnutrition and systemic inflammation status are involved in the prognosis of various cancers. In this study, we aimed to evaluate the prognostic value of the pretreatment fibrinogen-albumin ratio index (FARI) in nasopharyngeal carcinoma (NPC) patients receiving definite radiotherapy. NPC patients who received definite radiotherapy between January 2013 and December 2019 were included. A receiver operating characteristic (ROC) curve was used to determine the optimal cutoff value. The clinicopathological characteristics of the patients were compared via the Chi-square test. Survival curves were analyzed by the Kaplan‒Meier method. The prognostic factors were evaluated by univariate and multivariate analyses via Cox hazards regression analysis. A total of 225 patients were enrolled, and the median follow-up time was 48.5 months. High FARI was correlated with worse ECOG score (p = 0.003), higher EBV-DNA titer (p = 0.047), and more advanced clinical stage (p < 0.001). In the multivariable analysis, FARI independently predicted OS (HR 2.399, 95% CI 1.294–4.450, P < 0.001), PFS (HR 2.085, 95% CI 1.200–3.625, P = 0.009), and DMFS (HR 2.527, 95% CI 1.288–4.958, P < 0.001). The current findings suggest that a high pretreatment FARI is an independent predictor of OS, PFS and DMFS in NPC patients undergoing definite radiotherapy.


Patients
The data from patients diagnosed with NPC who underwent definitive radiotherapy, with or without chemotherapy, at the Second Xiangya Hospital, Central South University from January 2013 to December 2019 were retrospectively analyzed.The exclusion criteria were as follows: (1) patients with incomplete clinical-pathological data; (2) patients with missing laboratory test results; (3) patients with incomplete follow-up data; (4) patients with a history of chronic inflammatory diseases such as inflammatory bowel disease; and (5) patients with recent acute infectious diseases.The research was carried out in line with the Declaration of Helsinki and approved by the Ethics Committee of the Second Xiangya Hospital of Central South University, and informed consent was waived.

Data collection
The demographic and clinical pathological data and laboratory results were obtained from the hospital medical records system.Data regarding patients' age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS) scores, T stage, N stage, clinical stage, treatment modality, height, body weight, neutrophil, lymphocyte, platelet, monocyte, serum albumin, plasma fibrinogen, and EBV-DNA were collected.The plasma fibrinogen was tested via the Clauss method, and the serum albumin was tested via the bromocresol green method.The method of quality control is to use two levels of quality control products for machine testing, and the error should be within the range set by the laboratory.The FARI was calculated as follows: FARI = fibrinogen/albumin.

RT procedure
All patients were treated with intensity-modulated radiation therapy (IMRT).The gross tumor volume and clinical tumor volume were defined according to the guidelines 17 .The prescribed dose was 70 Gy/2.12Gy/33 F for PGTV, 60 Gy/1.82Gy/33 F for PTV1, and 54 Gy/1.64 Gy/33 F for PTV2.Radiotherapy was delivered once daily 5 days per week.Concurrent chemotherapy (cisplatin or nedaplatin) and targeted therapy (nimotuzumab) were administered according to the stage and tolerability of the patients.

Follow-up
Patients were followed up by telephone review or inpatient and outpatient medical records.The last follow-up date was April 30, 2023.Overall survival (OS) was calculated from the date of diagnosis to the date of death from any cause or to the last date of follow-up.Progression-free survival (PFS) was defined between the date of diagnosis and the date of disease progression or death.

Statistical analysis
SPSS statistical software (version 22.0; SPSS Inc., Chicago, IL, USA) was used for data analysis.Receiver operating characteristic (ROC) curves were used to calculate the cutoff value for FARI.The Chi-square test was used to analyze the relationship between FARI and clinicopathological features.The Kaplan-Meier method was used to calculate survival curves.Multivariate analysis was based on the Cox regression model.A two-sided p value < 0.05 was considered statistically significant.

Ethics statement
This research was carried out in line with the Declaration of Helsinki and approved by the Ethics Committee of the Second Xiangya Hospital of Central South University.The Ethics Committee of the Second Xiangya Hospital of Central South University waived the requirement of written informed consent.

Discussion
In the present study, we evaluated the prognostic importance of FARI in a cohort of 225 NPC patients.The results showed that high FARI was related to unfavorable clinical characteristics and outcomes.Furthermore, FARI was an independent prognostic factor of OS, PFS, and DMFS.To the best of our knowledge, this is the first report on the prognostic role of FARI in NPC patients.This result indicated that FARI may be a promising blood-based prognostic index for NPC patients.
Increasing evidence has shown that the systemic inflammatory response [18][19][20] and malnutrition [21][22][23] play a critical role in the development and progression of various malignancies.Fibrinogen is a classical coagulation-related protein; however, an increasing number of studies have proven that it is also a marker of systemic inflammation and is involved in the progression of cancer via multiple mechanisms.Fibrinogen could impair macrophage migration and prevent fibrinogen-leukocyte interactions by mutating the leukocyte integrin binding motif on fibrinogen, which harms the antitumor immunity of the host 24 .Fibrinogen could also block the ability of NK cells to clear tumor cells, facilitating evasion of immune surveillance and metastasis 25 .Fibrinogen could promote epithelial-mesenchymal transition (EMT) via the AKT-mTOR pathway 8 .Preclinical research has proven that suppression of fibrinogen by miRNA could decrease the metastatic potential of tumor cells in mouse lung cancer models 26 .Thus, decreasing fibrinogen might be a potential strategy to improve outcomes in cancer patients by minimizing metastasis.
Malnutrition is a common complication of cancer that is related to poorer quality of life, more treatment interruption, and worse prognosis 27 .Cancer-related symptoms, such as dysphagia and bowel obstruction, as well as cancer-induced excess catabolism and inflammation, could significantly affect nutritional status 28 .Albumin (ALB) is a typical repetitiveness of nutritional status that is synthesized by the liver and suppressed by malnutrition and systemic inflammation 29 .In clinical studies, ALB 30,31 and ALB-related indices, including the CRP-albumin ratio 32 and prognostic nutritional index 33 , have been proven to be independent prognostic factors in various cancers, including NPC.
FARI is a comparatively new marker of nutrition-inflammation status.Several studies have reported the prognostic value of FARI in many cancers, including esophageal squamous cell carcinoma 34 , hepatocellular carcinoma 35 , pancreatic neuroendocrine neoplasms 36 , and gastric cancer 37 .Although the cutoff value of FARI varies in different studies, all of the studies showed that elevated FARI is an adverse factor in cancer patients.This www.nature.com/scientificreports/result indicated that fibrinogen and albumin have consistent effects in different cancer patients.Our group previously also reported that FARI is an independent prognostic factor of OS in lung adenocarcinoma patients 38 and head and neck squamous cell carcinoma patients 13 .In the present study, we found that FARI is an independent prognostic factor of OS, PFS, and DMFS, but not LRRFS, in NPC patients.This result provides further support for the idea that the immune-inflammation status mainly affects the prognosis of cancer patients by influencing metastasis, not local relapse, which is in accordance with a previous report on mechanical and clinical research.
There are several limitations in this study.First, this is a single-center retrospective study with a long time span that may inherently carry some bias.Second, EBV-DNA has widely been accepted as a prognostic factor in Chinese patients.Some research has indicated that EBV-DNA > 4000 copies/ml predicts a worse prognosis in NPC patients 39 .However, the testing procedure of EBV-DNA has not been standardized thus far, which makes the results from different centers incomparable.In our center, the cutoff value of EBV-DNA is 400 ml/copy.In the present study, only 63.1% of the patients had an EBV-DNA test result.We found in univariate analysis that EBV-DNA was a prognostic factor with a cutoff value of 400 copies/ml.However, due to the limited sample size, it was not included in the multivariate analysis.Third, due to the limited sample size, no internal or external validation cohort was set to confirm the results.Therefore, more studies are still needed to further verify the clinical importance of FARI in NPC patients.

Conclusions
In summary, a high FARI level is related to poorer prognosis, and FARI is an independent factor of OS, PFS and DMFS in NPC patients.It is an effective and economical marker that may facilitate prognosis stratification and indicate a new perspective in intervention strategies to improve the clinical outcomes of NPC patients.

Figure 1 .
Figure 1.ROC curve of FARI in NPC patients.

Figure 2 .
Figure 2. Kaplan-Meier survival curves of NPC patients (A-D).(A) Kaplan-Meier curves for OS according to FARI; (B) Kaplan-Meier curves for PFS according to FARI; (C) Kaplan-Meier curves for LRRFS according to FARI; (D) Kaplan-Meier curves for DMFS according to FARI; OS overall survival, PFS progression free survival, LRRFS local-regional relapse-free survival, DMFS distant metastasis-free survival.

Table 1 .
The baseline clinicopathological characteristics of NPC patients (n = 225).ECOG PS eastern clinical oncology group performance status, BMI body mass index, CCRT concurrent chemoradiation therapy.

Table 2 .
Clinicopathological characteristics of 225 patients with NPC.ECOG PS Eastern clinical oncology group performance status, BMI body mass index, CCRT concurrent chemoradiation therapy.Significant values are in bold.

Table 3 .
Univariate analysis of potential factors associated with OS, PFS, LRRFS, and DMFS.ECOG PS Eastern clinical oncology group performance status, BMI body mass index, CCRT concurrent chemoradiation therapy, OS overall survival, PFS progression free survival, LRRFS local-regional relapse-free survival, DMFS distant metastasis-free survival.Significant values are in bold.

Table 4 .
Multivariable Cox regression analyses for OS, PFS, LRRFS, and DMFS.ECOG PS Eastern clinical oncology group performance status, CCRT concurrent chemoradiation therapy, OS overall survival, PFS progression-free survival, LRRFS local-regional relapse-free survival, DMFS distant metastasis-free survival.Significant values are in bold.